Fgfr inhibitor, preparation method therefor and application thereof

ABSTRACT

A compound having a structure of formula (I) and a preparation method therefor, and a use of the compound serving as an FGFR inhibitor for treating tumors, cancers, myeloproliferative diseases, bone or chondrocyte disorders, and hypophosphatemia.

TECHNICAL FIELD

The present invention belongs to the field of medicament synthesis, andin particular relates to an FGFR inhibitor, preparation method thereforand application thereof.

BACKGROUND

Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinasethat binds to fibroblast growth factor ligand. So far four FGFRs havebeen found to be bound to ligands and get closely involved in a varietyof physiological processes including tissue differentiation,angiogenesis, wound healing, and metabolic regulation. The binding ofligands to the receptors may result in dimerization and phosphorylationof the receptors, thereby stimulating the activation of protein kinaseactivity and recruiting numerous intracellular proteins to bind to. Theinteractions among these proteins promote the activation of a series ofintracellular signal pathways including Ras-MAPK, AKT-PI3K, andphosphatase C which are very important for cell growth, proliferationand survival.

The aberrant activation of these signal pathways, for example,over-expression of FGF ligands or the activating FGFR mutations may giverise to tumor growth, progression and resistance to conventional cancertherapies. The genetic changes, including gene amplification, chromosometranslocation and somatic mutation, that give rise to ligand-independentactivation of receptors have been described in human cancer. Large-scaleDNA sequencing of thousands of tumor samples has revealed that thecomponents of the FGFR signal pathway are susceptible to high-frequencymutation in human cancers. For example, somatic FGFR1 mutations havebeen identified in glioma and lung cancer; FGFR2 mutations are common ingastric cancer and endometrial cancer; FGFR3 mutations have beenidentified in bladder cancer and multiple myeloma; and FGFR4 mutationshave been identified in primary rhabdomyosarcoma.

FGF/FGFR related tumor types include but are not limited to cancers(e.g., bladder cancer, breast cancer, cervical spinal cancer, coloncancer, endometrial cancer, gastric cancer, head and neck cancer, renalcarcinoma, hepatic carcinoma, lung cancer, ovarian cancer, prostatecancer); haematological malignancy (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasm and Waldenstrommacroglobulinemia) and other tumors (e.g., glioblastoma, melanoma andrhabdomyosarcoma). In addition to its role in tumors, FGFR activationhas been found to be related to pathological changes of bones andcartilage cell, such as achondroplasia and craniosynostosis.

Although some FGFR inhibitors have been under clinical/preclinicaldevelopment, but they usually suffer from poor selectivity and showinhibition on other kinases like c-kit and PDGFRa, which to some extentraises concerns on therapeutic window of these inhibitors. In light ofthis, the development of selective inhibitors targeting FGFR is of greatsignificance in the clinical treatment of diseases with increased FGF orFGFR activities.

SUMMARY

The object of the present invention is to provide an FGFR inhibitor.

The first aspect of the invention provides a compound of formula (I), astereoisomer, prodrug or pharmaceutically acceptable salt thereof:

wherein, X is CH or N;

R₁ is selected from the group consisting of H, deuterium, hydroxy, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, —S(O)R₅, —S(O)₂R₆and —C(O)R₇, above groups are optionally further substituted by one ormore substituents selected from the group consisting of deuterium,halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;

R₂ is selected from the group consisting of C₃₋₁₀ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl and —NR₈R₉,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocyclyl, C₁₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;

each R₃ is independently selected from the group consisting of H,deuterium, halogen, cyano, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl. C₁₋₁₀haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;

each R₄ is independently selected from the group consisting of H,deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂, above groups are optionally further substituted byone or more substituents selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl,3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;

R₅ and R₆ are each independently selected from the group consisting ofH, deuterium, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl, 3-10 memberedheterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10membered heteroaryloxy and —NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, oxo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄;

R₇ is selected from the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10membered heterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,hydroxy, cyano, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy,C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxyand —NR₁₃R₁₄;

R₈ and R₉ are each independently selected from the group consisting ofdeuterium, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, —S(O)_(r)R₁₀,—C(O)R₁₂ and —C(O)NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,or, R₈ and R₉, together with the nitrogen atom directly attachedthereto, form a 4-10 membered heterocyclyl, above groups are optionallyfurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)R₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;

each R₁₀ is selected from the group consisting of H, deuterium, hydroxy,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy,C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 membered heteroaryl, 5-10 memberedheteroaryloxy and —NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, oxo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄;

each R₁₁ is selected from the group consisting of H, deuterium, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl and 5-10 membered heteroaryl, above groups are optionallyfurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, oxo, cyano, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 memberedheterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy,5-10 heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄;

each R₁₂ is selected from the group consisting of H, deuterium, hydroxy,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl, 3-10 memberedheterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10membered heteroaryloxy and —NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, cyano, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄;

R₁₃ and R₁₄ are each independently selected from the group consisting ofH, deuterium, hydroxy, C₁₋₁₀ alkoxy, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl,isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl,aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino,dialkylamino and C₁₋₁₀ alkanoyl, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl, C₁₋₁₀ alkoxy, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl, 3-10 memberedheterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C₁₋₁₀alkanoyl,

or, R₁₃ and R₁₁, together with the nitrogen atom directly attachedthereto, form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,hydroxy, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl,C₁₋₁₀ deuterioalkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy,3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl,C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxy, amino,monoalkylamino, dialkylamino and C₁₋₁₀ alkanoyl;

each r is independently 0, 1 or 2.

As a preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, R₁ isselected from the group consisting of H, deuterium, hydroxy, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,C₅₋₈ aryl, 5-8 membered heteroaryl, —S(O)R₅, —S(O)₂R₆ and —C(O)R₇, abovegroups are optionally further substituted by one or more substituentsselected from the group consisting of deuterium, halogen, cyano, nitro,azido. C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, ═O,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂;R₅, R₆, R₇, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r are defined as in the compoundof formula (I).

As a more preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, R₁ isselected from the group consisting of H, deuterium, C₁₋₄ alkyl, allyl,C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl, diazole, triazol,methylsulfonyl, isopropylsulfonyl, aminosulfonyl, methoxycarbonyl,ethoxycarbonyl, acetyl, aminocarbonyl and dimethylaminocarbonyl, abovegroups are optionally further substituted by one or more substituentsselected from the group consisting of deuterium, F, Cl, cyano, methyl,ethyl, C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl, methoxy,ethoxy, hydroxy, amino, isopropylamino, dimethylamino and diethyl amino.

As a preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, eachR₄ is independently selected from the group consisting of H, deuterium,halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀,—C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂,—C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂,—C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ andr are defined as in the compound of formula (I).

As a more preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, eachR₄ is independently selected from the group consisting of H, deuterium,halogen, cyano, nitro, azido. C₁₋₄ alkyl, allyl, acetenyl, C₃₋₆cycloalkyl, oxacyclobutyl, azacyclopentyl, azacyclohexyl, phenyl,diazole, triazol, methylsulfonyl, isopropylsulfonyl, aminosulfonyl,hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl,acetyl, acetoxy, acetoxymethyl, amino, dimethylamino and acetylamino,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, F, Cl,cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy andamino.

As a preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, eachR₃ is independently selected from the group consisting of H, deuterium,halogen, cyano. C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl,3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido. C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₅—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂,above groups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀,—C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂,—C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂,—C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ andr are defined as in the compound of formula (I).

As a preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, R₂ isC₅₋₈ aryl or 5-8 membered heteroaryl, above groups are optionallyfurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈aryl, 5-8 membered heteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁,—C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄,—C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and—C₀₋₄—N(R₁₃)—C(O)R₁₂, above groups are optionally more furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido. C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)R₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂;R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r are defined as in the compound of formula(I).

As a more preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, R₂ isphenyl or 5-6 membered heteroaryl, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,3-6 membered heterocyclyl, C₅₋₆ aryl, 5-6 membered heteroaryl, ═O,—S(O)_(r)R₁₀, —O—R₁₁, —C(O)OR₁₁, —C(O)R₁₂, —O—C(O)R₁₂, —NR₁₃R₁₄,—C(O)NR₁₃R₁₄ and —N(R₁₃)—C(O)R₁₂, above groups are optionally morefurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl,5-6 membered heteroaryl, ═O, —S(O)_(r)R₁₀, —O—R₁₁, —C(O)OR₁₁, —C(O)R₁₂,—O—C(O)R₁₂, —NR₁₃R₁₄, —C(O)NR₁₃R₁₄ and —N(R₁₃)—C(O)R₁₂; R₁₀, R₁₁, R₁₂,R₁₃, R₁₄ and r are defined as in the compound of formula (I).

As a more preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, R₂ isphenyl or 5-6 membered heteroaryl, the 5-6 membered heteroaryl isselected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazol and thiazolyl,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano. C₁₋₄ alkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,—S(O)_(r)R₁₀, —O—R₁₁, —C(O)OR₁₁, —NR₁₃R₁₄, —C(O)NR₁₃R₁₄ and—N(R₁₃)—C(O)R₁₂, above groups are optionally more further substituted byone or more substituents selected from the group consisting ofdeuterium, halogen, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, ═O,—S(O)_(r)R₁₀, —O—R₁₁ and —NR₁₃R₁₄; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r aredefined as in the compound of formula (I).

As a more preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, thecompound of formula (I) is a compound having formula (II):

wherein, X is CH or N;

R₁ is selected from the group consisting of H, deuterium, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl, methylsulfonyl andaminosulfonyl, above groups are optionally further substituted by one ormore substituents selected from the group consisting of deuterium, F,Cl, cyano, methyl, ethyl, C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl,phenyl, methoxy, ethoxy, hydroxy, amino, isopropylamino, dimethylaminoand diethyl amino;

R₂ is phenyl or 5-6 membered heteroaryl, the 5-6 membered heteroaryl isselected from the group consisting of pyridyl, pyrazolyl, imidazolyl andthiazolyl, above groups are optionally further substituted by one ormore substituents selected from the group consisting of deuterium,halogen, cyano, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, —NR₁₃R₁₄ and —C(O)NR₁₃R₁₄, above groups areoptionally more further substituted by one or more substituents selectedfrom the group consisting of deuterium, halogen, cyano, hydroxy, C₁₋₄alkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl,3-8 membered heterocyclyl, —S(O)_(r)R₁₀ and —NR₁₃R₁₄;

each R₃ is independently selected from the group consisting of H,deuterium, halogen, cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, oxacyclobutyl,azacyclopentyl, azacyclohexyl, hydroxy, methoxy, ethoxy and isopropoxy,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, C₁₋₄ alkyl, trifluoromethyl, difluoromethyl, trideuteriomethyl,dideuteriomethyl, cyclopropyl, oxacyclobutyl, methoxy, ethoxy, hydroxyand carboxy;

each R₄ is independently selected from the group consisting of H,deuterium, F, Cl, cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, oxacyclobutyl,azacyclopentyl, azacyclohexyl, hydroxy, methoxy, ethoxy and isopropoxy,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, F, Cl,cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy and hydroxy;

R₁₀, R₁₃, R₁₄ and r are defined as in the compound of formula (I).

As a more preferred embodiment, in the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, eachR₁₀ is selected from the group consisting of H, deuterium, hydroxy. C₁₋₄alkyl, C₁₋₄ alkoxy, C₂₋₄ alkenyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, 3-8membered heterocyclyl, 3-8 membered heterocyclyloxy, C₅₋₈ aryl, C₅₋₈aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and—NR₁₃R₁₄, above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, C₃₋₈cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy,C₅₋₈ aryl, C₅₋₈ aryloxy, 5-8 membered heteroaryl, 5-8 memberedheteroaryloxy and —NR₁₃R₁₄;

R₁₃ and R₁₄ are each independently selected from H, deuterium, hydroxy,C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl,3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, sulfinyl,sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl,p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino,monoalkylamino, dialkylamino and C₁₋₄ alkanoyl, above groups areoptionally further substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, hydroxy, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₁₋₄ alkoxy,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, 3-8 membered heterocyclyl, 3-8membered heterocyclyloxy, C₅₋₈ aryl, C₅₋₈ aryloxy, 5-8 memberedheteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino,dialkylamino and C₁₋₄ alkanoyl,

or, R₁₃ and R₁₄, together with the nitrogen atom directly attachedthereto, form a 4-8 membered heterocyclyl or 4-8 membered heteroaryl,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,hydroxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄deuterioalkyl, C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, 3-8membered heterocyclyl, 3-8 membered heterocyclyloxy, C₅₋₈ aryl, C₅₋₈aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino,monoalkylamino, dialkylamino and C₁₋₄ alkanoyl;

each r is independently 0, 1 or 2.

As the most preferred embodiment, the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereofincludes, but is not limited to, the following compounds:

The second aspect of the invention provides a process for preparing thecompound of formula (I), the stereoisomer, prodrug or pharmaceuticallyacceptable salt thereof, comprising the following steps:

wherein, X₁, X₂ are each independently Cl or Br; X, R₁, R₂, R₃ and R₄are defined as in the compound of formula (I).

The third aspect of the present invention provides a pharmaceuticalcomposition comprising the above compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof, andpharmaceutically acceptable carrier.

The fourth aspect of the present invention provides the application ofthe above compound of formula (I), the stereoisomer, prodrug orpharmaceutically acceptable salt thereof in the preparation ofmedicament for the treatment of tumor or cancer.

As a preferred embodiment, the tumor or cancer is selected from bladdercancer, breast cancer, cervical cancer, colorectal cancer, endometrialcancer, gastric cancer, head and neck cancer, renal carcinoma, hepaticcarcinoma, lung cancer, ovarian cancer, prostate cancer, esophagealcancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skincancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adultT cell leukemia, B cell lymphoma, acute myelocytic leukemia, Hodgkinlymphoma or non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, hairycell lymphoma, cell lymphoma, Bunkitt's lymphoma, glioblastoma, melanomaand rhabdomyosarcoma.

The fifth aspect of the present invention provides the applications ofthe above compound of formula (I), the stereoisomer, prodrug orpharmaceutically acceptable salt thereof in the preparation ofmedicament for the treatment of myeloproliferative disease, skeleton orcartilage cell disorder, and hypophosphatemia.

As a preferred embodiment, the myeloproliferative disease is selectedfrom polycythemia, primary thrombocytosis or primary myelofibrosis; theskeleton or cartilage cell disorder is selected from dysplasia,dyschondroplasia, dwarfism, thanatophoric dysplasia (TD), Apert'ssyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrata syndrome, Pfeiffer syndrome or cranial muscular atrophysyndrome; the hypophosphatemia is selected from X-linkedhypophosphatemic rickets, autosomal recessive hypophosphatemic rickets,autosomal dominant hypophosphatemic rickets and tumor inducedoothecomalacia.

The sixth aspect of the present invention provides the compound offormula (I), the stereoisomer, prodrug or pharmaceutically acceptablesalt thereof or the pharmaceutical composition for use as a selectiveFGFR inhibitor for the treatment of diseases related to the aberrantexpression/mutation of FGFR or the aberrant expression/activity ofcorresponding ligand(s).

DETAILED DESCRIPTION OF THE INVENTION

After an extensive and intensive research, the inventor of the presentinvention developed an FGFR inhibitor of structure as shown in formula(I), preparation method therefor and application thereof for the firsttime. The substituents are defined as and described in the specificationand the claims. The series of compounds in this invention can be widelyused for developing a promising new generation of FGFR inhibitormedicament for treating tumor, cancer, myeloproliferative disease,skeleton or cartilage cell disorder, and/or hypophosphatemia. On suchbasis, the present invention has been completed.

Detailed description: Unless otherwise stated, the following terms usedin the specification and claims have the following meanings.

“Alkyl” refers to a straight or branched saturated aliphatic hydrocarbongroup, for example, “C₁₋₈ alkyl” refers to a straight or branched alkylhaving 1 to 8 carbon atoms, including but is not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl,n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl,n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl,3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl or various branched isomers thereof and so on.

The alkyl can optionally be either a substituted or unsubstituted one;if it is a substituted one, the substituents can preferably be one ormore (preferably 1, 2, 3 or 4) of the following groups, andindependently selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Cycloalkyl” refers to a saturated or partially unsaturated monocyclicor polycyclic hydrocarbon substituent, for example, “C₃₋₁₀ cycloalkyl”refers to a cycloalkyl having 3-10 carbon atoms, which may be amonocyclic cycloalkyl and a polycyclic cycloalkyl, wherein,

monocyclic cycloalkyl includes, but is not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and thelike;

and polycyclic cycloalkyl includes spiro, fused, and bridgedcycloalkyls. “Spirocycloalkyl” refers to a polycyclic group that sharesa carbon atom (called a spiro atom) between the monocyclic rings. Thesegroups may contain one or more (preferably 1, 2 or 3) double bonds, butnone of the rings have a fully conjugated π-electron system. Thespirocycloalkyl may be a monospirocycloalkyl, a bispirocycloalkyl or apolyspirocycloalkyl according to the number of common spiro atomsbetween the rings, spirocycloalkyl includes, but is not limited to:

“Fused cycloalkyl” refers to an all-carbon polycyclic group in whicheach ring shares an adjacent pair of carbon atoms with other rings inthe system, wherein one or more (preferably 1 or 2) of the rings maycontain one or more (preferably 1, 2 or 3) double bonds, but none of therings have a fully conjugated n-electron system. Depending on the numberof rings, it may be bicyclic, tricyclic, tetracyclic or polycyclic,fused cycloalkyl includes but is not limited to:

“Bridged cycloalkyl” refers to an all-carbon polycyclic group in whichany two rings share two carbon atoms that are not directly bonded, whichmay contain one or more (preferably 1, 2 or 3) double bonds, but none ofthe rings have a fully conjugated π-electron system. Depending on thenumber of rings, it may be bicyclic, tricyclic, tetracyclic orpolycyclic, bridged cycloalkyl includes but is not limited to: Dependingon the number of rings, it may be bicyclic, tricyclic, tetracyclic orpolycyclic, fused cycloalkyl includes but is not limited to:

The ring of the cycloalkyl may be fused to a ring of aryl, heteroaryl orheterocycloalkyl, wherein the ring attached to the parent structure is acycloalkyl, includes, but is not limited to indanyl, tetrahydronaphthyl,benzocycloheptyl and the likes.

The cycloalkyl can optionally be either a substituted or unsubstitutedone: if it is a substituted one, the substituents can preferably be oneor more (preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Heterocyclyl” refers to a saturated or partially unsaturated monocyclicor polycyclic cyclic hydrocarbon substituent wherein one or more(preferably 1, 2, 3 or 4) of the ring atoms are heteroatoms selectedfrom nitrogen, oxygen or S(O)_(r) (wherein r is an integer of 0, 1, 2),but excluding ring moiety of —O—O—, —O—S— or —S—S—, and the remainingring atoms are carbon atoms. For example, “5-10 membered heterocyclyl”refers to a cyclic group containing 5 to 10 ring atoms, and “3-10membered heterocyclyl” refers to a cyclic group containing 3 to 10 ringatoms.

Monocyclic heterocyclyl includes, but is not limited to pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyland the likes.

and polycyclic heterocyclyl includes spiro, fused, and bridgedheterocyclyls. “Spiroheterocyclyl” refers to a polycyclic heterocyclylthat shares a carbon atom (called a spiro atom) between the monocyclicrings, wherein one or more (preferably 1, 2, 3 or 4) of the ring atomsare heteroatoms selected from nitrogen, oxygen or S(O)_(r) (wherein r isan integer of 0, 1, 2), and the remaining ring atoms are carbon atoms.These groups may contain one or more (preferably 1, 2 or 3) doublebonds, but none of the rings have a fully conjugated π-electron system.The spiroheterocyclyl may be a monospiroheterocyclyl, abispiroheterocyclyl or a polyspiroheterocyclyl according to the numberof common spiro atoms between the rings, spiroheterocyclyl includes, butis not limited to:

“Fused heterocyclyl” refers to a polycyclic heterocyclyl in which eachring shares an adjacent pair of carbon atoms with other rings in thesystem, wherein one or more (preferably 1 or 2) of the rings may containone or more (preferably 1, 2 or 3) double bonds, but none of the ringshave a fully conjugated π-electron system, wherein one or more(preferably 1, 2, 3 or 4) of the ring atoms are heteroatoms selectedfrom nitrogen, oxygen or S(O)_(r) (wherein r is an integer of 0, 1, 2),and the remaining ring atoms are carbon atoms. Depending on the numberof rings, it may be bicyclic, tricyclic, tetracyclic or polycyclic,fused heterocyclyl includes, but is not limited to:

“Bridged heterocyclyl” refers to a polycyclic heterocyclyl in which anytwo rings share two carbon atoms that are not directly bonded, which maycontain one or more (preferably 1, 2 or 3) double bonds, but none of therings have a hilly conjugated pi-electron system, wherein one or more(preferably 1, 2, 3 or 4) of the ring atoms are heteroatoms selectedfrom nitrogen, oxygen or S(O)_(r) (wherein r is an integer of 0, 1, 2),and the remaining ring atoms are carbon atoms. Depending on the numberof rings, it may be bicyclic, tricyclic, tetracyclic or polycyclic,bridged heterocyclyl includes, but is not limited to:

The ring of the heterocyclyl may be fused to a ring of aryl, heteroarylor cycloalkyl wherein the ring attached to the parent structure is aheterocyclyl, includes, but is not limited to:

The heterocyclyl can optionally be either a substituted or unsubstitutedone; if it is a substituted one, the substituents can preferably be oneor more (preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Aryl” refers to an all-carbon monocyclic or fused polycyclic (ie, aring that shares a pair of adjacent carbon atoms) group, and apolycyclic group having a conjugated π-electron system (i.e., a ringwith adjacent pairs of carbon atoms), for example, “C₅₋₁₀ aryl” refersto an all-carbon aryl having 5-10 carbons, and “5-10 membered aryl”refers to an all-carbon aryl having 5-10 carbons, including but notlimited to phenyl and naphthyl. The aryl ring may be fused to a ring ofheteroaryl, heterocyclyl or cycloalkyl, wherein the ring attached to theparent structure is an aryl ring, includes, but is not limited to:

The aryl can optionally be either a substituted or unsubstituted one; ifit is a substituted one, the substituents can preferably be one or more(preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Heteroaryl” refers to a heteroaromatic system containing 1 to 4heteroatoms including a hetero atom selected from nitrogen, oxygen orS(O)r (wherein r is an integer of 0, 1, 2), for example, 5-8 memberedheteroaryl refers to a heteroaromatic system containing 5 to 8 ringatoms, and 5-10 membered heteroaryl refers to a heteroaromatic systemcontaining 5 to 10 ring atoms, including but not limited to furyl,thiophenyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl,imidazolyl, tetrazolyl group or the like. The heteroaryl ring may befused to a ring of aryl, heterocyclyl or cycloalkyl wherein the ringattached to the parent structure is a heteroaryl ring, includes, but isnot limited to:

The heteroaryl can optionally be either a substituted or unsubstitutedone; if it is a substituted one, the substituents can preferably be oneor more (preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Alkenyl” refers to an alkyl group defined as above consisting of atleast two carbon atoms and at least one carbon-carbon double bond, forexample, C₂₋₈ alkenyl refers to a straight or branched alkenylcontaining 2 to 8 carbons. Alkenyl includes, but is not limited tovinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the likes.

The alkenyl can be either a substituted or unsubstituted one; if it is asubstituted one, the substituents can preferably be one or more(preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Alkynyl” refers to an alkyl group defined as above consisting of atleast two carbon atoms and at least one carbon-carbon triple bond, forexample, C₂₋₈ alkynyl refers to a straight or branched alkynylcontaining 2 to 8 carbons. Alkynyl includes, but is not limited toethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the likes.

The alkynyl can be either a substituted or unsubstituted one; if it is asubstituted one, the substituents can preferably be one or more(preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Alkoxy” refers to —O-(alkyl), wherein alkyl is defined as above, forexample, “C₁₋₈ alkoxy” refers to an alkyloxy containing 1 to 8 carbons.Alkoxy includes, but is not limited to methoxy, ethoxy, propoxy, butoxy,and the likes.

The alkoxy can optionally be either a substituted or unsubstituted one;if it is a substituted one, the substituents can preferably be one ormore (preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“Cycloalkyloxy” refers to —O-(unsubstituted cycloalkyl), whereincycloalkyl is defined as above, for example, “C₃₋₁₀ cycloalkyloxy”refers to a cycloalkyloxy containing 3 to 10 carbon atoms. Cycloalkyloxyincludes, but is not limited to, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and the likes.

The cycloalkoxy can optionally be either a substituted or unsubstitutedone; if it is a substituted one, the substituents can preferably be oneor more (preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“3-10 membered heterocyclyloxy” refers to and —O-(unsubstituted 3-10membered heterocyclyl), wherein the definition of 3-10 memberedheterocyclyl is as above-mentioned; 3-10 membered heterocyclyloxy canoptionally be either a substituted or unsubstituted one; if it is asubstituted one, the substituents can preferably be one or more(preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“C₅₋₁₀ aryloxy” refers to and —O-(unsubstituted C₅₋₁₀ aryl), wherein thedefinition of C₅₋₁₀ aryl is as above-mentioned; C₅₋₁₀ aryloxy canoptionally be either a substituted or unsubstituted one; if it is asubstituted one, the substituents can preferably be one or more(preferably 1, 2, 3 or 4) of the following groups, independentlyselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂.

“5-10 heteroaryloxy” refers to and —O-(unsubstituted 5-10 memberedheteroaryl), wherein the definition of 5-10 membered heteroaryl is asabove-mentioned; 5-10 membered heteroaryloxy can optionally be either asubstituted or unsubstituted one; if it is a substituted one, thesubstituents can preferably be one or more (preferably 1, 2, 3 or 4) ofthe following groups, independently selected from the group consistingof deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl,3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂.

“C₁₋₈ alkanoyl” refers to a monovalent group obtained by removinghydroxy from C₁₋₈ alkyl acid, is also generally referred to as“C₀₋₇—C(O)—”, for example, “C₁—C(O)—” refers to acetyl; “C₂—C(O)—”refers to propionyl; and “C₃—C(O)—” refers to butyryl or isobutyryl.

“—C₀₋₈—S(O)_(r)R₁₀” means that the sulfur atom in —S(O)_(r)R₁₀ is bondedto C₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is definedas above.

“—C₀₋₈—O—R₁₁” means that the oxygen atom in —O—R₁₁ is bonded to C₀₋₈alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—C(O)OR₁₁” means that the carbonyl group in —C(O)OR₁₁ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—C(O)R₁₂” means that the carbonyl group in —C(O)R₁₂ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—O—C(O)R₁₂” means that the oxygen atom in —O—C(O)R₁₂ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—NR₁₃R₁₄” means that the nitrogen atom in —NR₁₃R₁₄ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—C(═NR₁₃)R₁₂” means that the carbonyl in —C(═NR₁₃)R₁₂ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂” means that the carbonyl in—N(R₁₃)—C(═NR₁₄)R₁₂ is bonded to C₀₋₈ alkyl, wherein C₀ alkyl means abond, and C₁₋₈ alkyl is defined as above.

“—C₀₋₈—C(O)NR₁₃R₁₄” means that the carbonyl in —C(O)NR₁₃R₁₄ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is defined asabove.

“—C₀₋₈—N(R₁₄)—C(O)R₁₃” means that the nitrogen atom in —N(R₁₄)—C(O)R₁₃is bonded to C₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkylis defined as above.

“C₁₋₈ haloalkyl” refers to a alkyl group having 1 to 8 carbon atoms,wherein any hydrogen atom on which is optionally substituted with F, Cl,Br or I, and includes, but is not limited to difluoromethyl,dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl,tribromomethyl, and the likes.

“C₁₋₈ haloalkoxy” means an alkoxy having 1 to 8 carbon atoms, whereinany hydrogen atom on which is optionally substituted with F, Cl, Br orI, and includes, but is not limited to difluoromethoxy, dichloromethoxy,dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, andthe likes.

“Halogen” means F, Cl, Br or I. “THF” refers to tetrahydrofuran. “MeOH”means methanol. “DMF” means N,N-dimethylformamide. “THF” meanstetrahydrofuran. “PE” means petroleum ether. “EA/EtOAc” means ethylacetate. “DCM” means dichloromethane. “DIPEA” meansN,N-diisopropylethylamine. “LAH/LiAlH₄” means lithium aluminum hydride.“MnO₂” means manganese dioxide. “K₂CO₃” means potassium carbonate.“K₃PO₄” means potassium phosphate. “Cs₂CO₃” means cesium carbonate.“Na₂CO₃” means sodium carbonate. “NaHCO₃” means sodium bicarbonate.“SO₂Cl₂” means thionyl chloride. “NBS” means N-bromo-succinimide.“i-PrMgCl” means isopropyl magnesium chloride. “Select-F” means1-chloromethyl-4-fluoro-1,4-diazoniabicyclo 2,2,2 octaneBis(tetrafluoroborate).

“Optional” or “optionally” means that the event or environmentsubsequently described may, but need not, occur, including where theevent or environment occurs or does not occur. For example,“heterocyclyl optionally substituted by alkyl” means that an alkyl groupmay be, but is not necessarily, present, and the description includesthe case where the heterocyclyl is substituted with an alkyl and thecase where the heterocyclyl is not substituted with an alkyl.

“Substituted” means that one or more (preferably 1, 2, 3 or 4) hydrogenatoms in a group are each independently substituted with a correspondingnumber of substituents. It goes without saying that a substituent isonly in its possible chemical position, and those skilled in the artwill be able to determine (by experiment or theory) possible orimpossible substitution without undue efforts. For example, it may beunstable that an amino group or a hydroxy group having a free hydrogenis attached with a carbon atom having an unsaturated bond (such as anolefin).

“Pharmaceutical composition” means a mixture comprising one or more ofthe compounds described herein, or a physiologically/pharmaceuticallyacceptable salt or pro-drug thereof, and other chemical components, forexample physiological/pharmaceutically acceptable carriers andexcipients. The purpose of the pharmaceutical composition is to promotethe administration to an organism, which facilitates the absorption ofthe active ingredient thereby exerting biological activities.

The present invention will be further described in detail below inconjunction with the embodiments which is not intended to limit thepresent invention. The present invention is also not limited to thecontents of the embodiments.

The structure of the compound of the present invention is determined bynuclear magnetic resonance (NMR) or/and liquid chromatography-massspectrometry (LC-MS). The NMR chemical shift (5) is given in parts permillion (ppm). The NMR is measured by a Bruker AVANCE-400/500 nuclearmagnetic apparatus, and the solvent is deuterated dimethyl sulfoxide(DMSO-d₆), deuterated methanol (CD₃OD) and deuterated chloroform(CDCl₃), and the internal standard is tetramethylsilane (TMS).

The measurement of LC-MS is performed by using an Agilent 6120 massspectrometer. The measurement of HPLC is performed by using an Agilent1200 DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mmcolumn) and a Waters 2695-2996 high pressure liquid chromatograph(Gimini C18 150×4.6 mm column).

The thin layer chromatography silica gel plate is Yantai Yellow SeaHSGF254 or Qingdao GF254 silica gel plate. The specification of TLC is0.15 mm-0.20 mm, and the specification for thin layer chromatographyseparation and purification is 0.4 mm-0.5 mm. 200-300 mesh silica gel(Yantai Huanghai silica gel) as a carrier is generally used in columnchromatography.

The starting materials in the examples of the present invention areknown and commercially available or can be synthesized according tomethods known in the art.

Unless otherwise stated, all reactions of the present invention arecarried out under continuous magnetic stirring under a dry nitrogen orargon atmosphere, the solvent is a dry solvent, and the unit of thereaction temperature is degrees Celsius (° C.).

I. Preparation of Intermediates 1. Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one

Step 1: Synthesis of ethyl 6-chloro-4-(ethylamino)nicotinate

N,N-diisopropylethylamine (8.78 g, 27.3 mmol) and ethylamine (1.76 g,27.3 mmol, 70% aqueous solution) was added into a solution of ethyl4,6-dichloronicotinate (5.00 g, 22.7 mmol) in acetonitrile (70 mL). Thereaction solution was stirred at 70° C. for 18 hours. Then the reactionsolution was cooled down, diluted with ethyl acetate (200 mL), washedwith saturated salt solution (150 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated to obtain ethyl6-chloro-4-(ethylamino)nicotinate (5.20 g, yield: 100%). MS m/z (ESI):229.2 [M+H]⁺.

Step 2: Synthesis of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol

Ethyl 6-chloro-4-(ethylamino)nicotinate (5.00 g, 22.7 mmol) wasdissolved in tetrahydrofuran (70 mL), and LiAlH₄ (1.73 g, 44.48 mmol)was added slowly in batches under an iced bath. The reaction solutionwas stirred under an iced bath for 1 hour. The reaction solution wasquenched with sodium sulfate decahydrate, stirred at room temperaturefor 1 hour and filtrated. The filtrate was concentrated to obtain(6-chloro-4-(ethylamino)pyridin-3-yl)methanol (4.20 g, yield: 99%). MSm/z (ESI): 187.2 [M+H]⁺.

Step 3: Synthesis of 6-chloro-4-(ethylamino)nicotinaldehyde

(6-chloro-4-(ethylamino)pyridin-3-yl)methanol (4.2 g, 22.5 mmol) wasdissolved in a mixed solvent of dichloromethane (50 mL) andtetrahydrofuran (50 mL), and then MnO₂ (23.5 g, 270 mmol) was added. Thereaction solution was stirred overnight at room temperature, filtratedand washed with ethyl acetate. The filtrate was concentrated to obtain6-chloro-4-(ethylamino)nicotinaldehyde (3.5 g, yield: 84%). MS m/z(ESI): 185.0 [M+H]⁺.

Step 4: Synthesis of7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one

K₂CO₃ (2.24 g, 16.24 mmol) was added into a solution of6-chloro-4-(ethylamino)nicotinaldehyde (1.50 g, 8.12 mmol) and ethyl2-(3,5-dimethoxyphenyl)acetate (1.82 g, 8.12 mmol) inN,N-dimethylformamide (50 mL). The reaction solution was stirred at 110°C. for 17 hours. Afterwards, the reaction solution was cooled down toroom temperature, poured into water and filtrated. The filter cake wasdried to obtain7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one(2.30 g, yield: 82%). MS m/z (ESI): 345.0 [M+H]⁺.

Intermediates 2˜8 were Prepared According to the Synthesis Method ofIntermediate 1

MS Intermediate [M + H]⁺. No. Structural Formula Chemical name m/z(ESI): 2

7-chloro-3-(3,5- dimethoxyphenyl)-1- methyl-1,6-naphthyridin- 2(1H)-one331.1 3

7-chloro-3-(3,5- dimethoxyphenyl)-1- isopropyl-1,6-naphthyridin-2(1H)-one 359.4 4

7-chloro-1- (cyclopropylmethyl)-3-(3,5- dimethoxyphenyl)-1,6-naphthyridin-2(1H)-one 371.4 5

7-chloro-3-(3,5- dimethoxyphenyl)-1-(2- morpholinoethyl)-1,6-naphthyridin-2(1H)-one 430.1 6

7-chloro-3-(3,5- dimethoxyphenyl)-1-(2- (dimethylamino)ethyl)-1,6-naphthyridin-2(1H)-one 388 7

7-chloro-3-(3,5- dimethoxyphenyl)-1- (tetrahydrofuran-3-yl)-1,6-naphthyridin-2(1H)-one 387 8

7-chloro-3-(3,5- dimethoxyphenyl)-1- (oxetane-3-yl)-1,6-naphthyridin-2(1H)-one 373

9. Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one

A solution of7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (500mg, 1.45 mmol) in acetonitrile (8 mL) was cooled down to −30° C., andthen SO₂Cl₂ (640 mg, 3.62 mmol) was added dropwise slowly. The reactionsolution was stirred at −30° C. for 30 minutes. Afterwards, the reactionsolution was quenched with saturated sodium bicarbonate and filtrated.The filter cake was washed and dried to obtain7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one(520 mg, yield: 87%). MS m/z (ESI): 413.2, 415.2[M+H]⁺.

Intermediates 10˜16 were Prepared According to the Synthesis Method ofIntermediate 9

MS Intermediate [M + H]⁺. No. Structural Formula Chemical name m/z(ESI): 10

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin- 2(1H)-one 398.7, 400.7 11

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1- isopropyl-1,6-naphthyridin-2(1H)-one 427.2, 429.2 12

7-chloro-1- (cyclopropylmethyl)-3- (2,6-dichloro-3,5-dimethoxyphenyl)-1,6- naphthyridin-2(1H)-one 439.2, 441.2 13

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1-(2-morpholinoethyl)-1,6- naphthyridin-2(1H)-one 498.3, 500.3 14

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1- (2-(dimethylamino)ethyl)- 1,6-naphthyridin-2(1H)- one 456, 458 15

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1-(tetrahydrofuran-3-yl)- 1,6-naphthyridin-2(1H)- one 455, 457 16

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1- (oxetane-3-yl)-1,6-naphthyridin-2(1H)-one 441, 443

17. Preparation of7-chloro-1-ethyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1,6-naphthyridin-2(1H)-one

Select-F (370 mg, 1.044 mmol) was added to a solution of7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (300mg, 0.870 mmol) in acetonitrile at −15° C. The reaction solution waswarmed to room temperature slowly and stirred for 1 hour. Then thereaction solution was cooled down to −15° C. again, and additionalselect-F (300 mg, 0.847 mmol) was added. The reaction solution was thenslowly warmed to room temperature and stirred for 50 minutes. Thereaction solution was diluted with DCM and washed with saturated NaHCO₃solution, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and then separated by column chromatography(PE:EtOAc=0-17%) to obtain7-chloro-1-ethyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1,6-naphthyridin-2(1H)-one(223 mg, purity: 76%). The crude product (80 mg) was separated by PTLC(PE/EtOAc=8:1) to obtain7-chloro-1-ethyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1,6-naphthyridin-2(1H)-one(43 mg). MS m/z (ESI): 363.2 [M+H]⁺.

18. Preparation of7-chloro-3-(2-chloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one

A solution of7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (200mg, 0.58 mmol) in acetonitrile (5 mL) was cooled down to −30° C., andthen SO₂Cl₂ (86 mg, 0.64 mmol) was slowly added dropwise. The reactionsolution was stirred at −30° C. for 20 minutes. Afterwards, the reactionsolution was quenched with saturated sodium bicarbonate, extracted withethyl acetate and concentrated. The residue was separated by columnchromatography (EA/DCM=0%-10%) to obtain7-chloro-3-(2-chloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one(165 mg, yield: 75%). MS m/z (ESI): 379.2, 381.2[M+H]⁺.

19. Preparation of4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine

Cs₂CO₃ (3.35 g, 10.3 mmol) was added into a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15mmol) and 4-(2-bromoethyl)morpholine bromide (1.40 g, 7.72 mmol) inN,N-dimethylformamide (8 mL). The reaction solution was stirred at 100°C. for 17 hours. The suspension was filtrated, and the filtrate wasseparated by a reverse-phase column chromatography (CH₃CN:H₂O=0%-15%) toobtain4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine(1.1 g, yield: 70%). MS m/z (ESI): 308.2 [M+H]⁺.

20. Preparation of3-bromo-1-ethyl-7-(l-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

Step 1: Synthesis of7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic Acid

2,2-dimethyl-1,3-dioxan-4,6-dione (546 mg, 3.79 mmol), piperidine (32mg, 0.38 mmol) and acetic acid (68 mg, 1.14 mmol) were added into asolution of 6-chloro-4-(ethylamino)nicotinaldehyde (700 mg, 3.79 mmol)in ethanol (7 mL). The reaction solution refluxed for 3 hours.Afterwards, the reaction solution was cooled down to room temperatureand filtrated. The filter cake was washed with ethanol and then dried toobtain 7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylicacid (850 mg, yield 89%). MS m/z (ESI): 253.2 [M+H]⁺.

Step 2: Synthesis of1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylicAcid

[1,1-bis(diphenylphosphino)ferrocene] palladium bichloride (246 mg, 0.34mmol) and Na₂CO₃ (2N, 5 mL) were added into a solution of7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-carboxylic acid(850 mg, 3.36 mmol) and 1-methyl-1H-pyrazol-4-borate (848 mg, 6.73 mmol)in 1,4-dioxane (15 mL). The suspension was stirred at 95° C. for 16hours. Afterwards, the suspension was cooled down to room temperature,added with water and extracted with ethyl acetate. The water phase wasadjusted to pH 2˜3 with 2N hydrochloric acid and the precipitate wasfiltrated. The filter cake was washed with ethanol and then dried toobtain1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylicacid (950 mg, yield: 95%). MS m/z (ESI): 299.2 [M+H]⁺.

Step 3: Synthesis of3-bromo-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-carboxylicacid (400 mg, 1.34 mmol) was dissolved in a mixed solution ofN,N-dimethylformamide (18 mL) and water (2 mL), and thenN-bromo-succinimide (477 mg, 2.68 mmol) and lithium acetate (273 mg,2.68 mmol) were added. The reaction solution was subjected to microwavereaction at 110° C. for 3 hours. Afterwards, the reaction solution wascooled down to room temperature, diluted with water, extracted withethyl acetate and washed with saturated salt solution. The organic phasewas concentrated and separated by column chromatography (ethylacetate/dichloromethane=0˜20%) to obtain3-bromo-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2 (1H)-one(150 mg, yield: 34%). MS m/z (ESI): 333.2, 335.2[M+H]⁺.

Intermediates 21˜27 were Prepared According to the Synthesis Method ofIntermediate 20

MS Intermediate [M + H]⁺. No. Structural Formula Chemical name m/z(ESI): 21

3-bromo-1-isopropyl-7-(1- methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one 347, 349 22

3-bromo-1- (cyclopropylmethyl)-7-(1- methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one 359, 361 23

3-bromo-1-(2- (dimethylamino)ethyl)-7-(1- methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one 376, 378 24

3-bromo-7-(1-methyl-1H- pyrazol-4-yl)-1- (tetrahydrofuran-3-yl)-1,6-naphthyridin-2(1H)-one 375, 377 25

3-bromo-1-ethyl-7-(1-(2- morpholinoethyl)-1H- pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one 432, 434 26

3-bromo-1-isopropyl-7-(1- (2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one 446, 448 27

3-bromo-1-ethyl-7-(3- methyl-1-(2- morpholinoethyl)-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)-one 446, 448

28. Preparation of2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Isopropylmagnesium chloride solution (2.0 mL, 4.0 mmol, in 2Ntetrahydrofuran) was slowly added into a solution of2,4-difluoro-3-iodo-1,5-dimethoxybenzene (1.00 g, 3.33 mmol) intetrahydrofuran (15 mL) at −10° C. The reaction solution was stirred at−10° C. for 10 minutes, and then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (805 mg, 4.33 mmol)was added. Afterwards, the reaction solution was stirred at roomtemperature for 2 hours, quenched with saturated ammonium chloridesolution, extracted with ethyl acetate. The organic phase was washedwith water, dried, concentrated and separated by column chromatography(EA/DCM=0˜20%) to obtain2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(800 mg, yield: 80%). MS m/z (ESI): 301.0 [M+H]⁺.

II. Preparation of Specific Examples Example 1. Preparation of3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

An aqueous solution of [1,1′-bis(diphenylphosphino)ferrocene]palladiumbichloride (9 mg, 0.012 mmol) and Na₂CO₃ (0.5 mL, 1.0 mmol, 2N) wasadded into a solution of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one(50 mg, 0.12 mmol) and 1-methyl-1H-pyrazol-4-borate (30 mg, 0.24 mmol)in 1,4-dioxane (2 mL). The reaction solution was stirred at 95° C. for16 hours. Afterwards, the reaction solution was cooled down to roomtemperature, added with water a nd extracted with ethyl acetate. Theorganic phase was concentrated and the residue was separated by PTLC(EA/DCM=1/2) to obtain3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one(35 mg, yield: 63%) MS m/z (ESI): 459.4, 461.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.64(s, 1H), 7.35 (s, 1H), 6.65 (s, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.01 (s,3H), 3.96 (s, 6H), 1.43 (t, J=7.0 Hz, 3H).

Examples 2˜24 were Prepared According to the Synthesis Method of Example1

Example No. Structural Formula Chemical name MS m/z (ESI): [M +H]⁺/¹HNMR 2

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI): 445.4, 447.4[M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.08 (s, 1H), 8.05 (s,1H), 7.64 (s, 1H), 7.33 (s, 1H), 6.64 (s, 1H), 4.00 (s, 3H), 3.96 (s,6H), 3.79 (s, 3H). 3

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- isopropyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI): 473.4, 475.4[M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 8.16 (s, 1H), 8.02 (s,1H), 7.59 (s, 1H), 7.52 (s, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.95 (s,6H), 3.49 (d, J = 3.3 Hz, 1H), 1.71 (d, J = 6.8 Hz, 6H). 4

1-(cyclopropylmethyl)- 3-(2,6-dichloro-3,5- dimethoxyphenyl)-7-(1-methyl-1H-pyrazol- 4-yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI):485.0, 487.0 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 8.23 (brs, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 6.64 (s, 1H), 4.31 (d,J = 7.0 Hz, 2H), 4.01 (s, 3H), 3.95 (s, 6H), 1.33-1.25 (m, 1H),0.62-0.54 (m, 4H). 5

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7- (1-methyl-1H-pyrazol-4-yl)-1-(2- morpholinoethyl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI):544.4, 546.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.03 (brs, 2H), 7.65 (s, 1H), 7.40 (br s, 1H), 6.64 (s, 1H), 4.50 (br s, 2H),4.00 (s, 3H), 3.95 (s, 6H), 3.69 (br s, 4H), 2.75 (br s, 2H), 2.60 (brs, 4H). 6

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- (2- (dimethylamino)ethyl)-7-(1-methyl-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI):502.3, 504.3 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.77 (s,1H), 8.32 (s, 1H), 8.19 (s, 1H), 7.71 (s, 1H), 6.65 (s, 1H), 4.95 (t, J= 8.0 Hz, 2H), 4.01 (s, 3H), 3.95 (s, 6H), 3.39-3.27 (m, 2H), 2.92 (s,6H). 7

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7- (1-methyl-1H-pyrazol- 4-yl)-1-(tetrahydrofuran-3-yl)- 1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 501,503 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (s, 1H), 8.07 (s, 1H), 8.06(s, 1H), 8.02 (s, 1H), 7.60 (s, 1H), 6.64 (s, 1H), 6.42- 6.35 (m, 1H),4.56-4.52 (m, 1H), 4.28 (dd, J = 10.4, 4.1 Hz, 1H), 4.07 (t, J = 9.9 Hz,1H), 3.99 (s, 3H), 3.95 (s, 6H), 3.88- 3.81 (m, 1H), 2.49-2.33 (m, 2H).8

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7- (1-methyl-1H-pyrazol-4-yl)-1-(oxetan-3-yl)- 1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 487.2,489.2 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 8.27 (s, 1H),7.98 (s, 1H), 7.67 (s, 1H), 6.97 (s, 1H), 6.65 (s, 1H), 5.72-5.61 (m,1H), 5.16 (t, J = 7.3 Hz, 2H), 4.98 (t, J = 7.5 Hz, 2H), 4.01 (s, 3H),3.96 (s, 6H). 9

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7- (1,3-dimethyl-1H-pyrazol-4-yl)-1-ethyl- 1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 473.2,475.2 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.19 (br s, 1H),7.65 (s, 1H), 7.36 (s, 1H), 6.65 (s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.96(s, 6H), 3.93 (s, 3H), 2.61 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). 10

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- ethyl-7-(1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 558.4, 560.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H),8.07 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 6.57 (s, 1H),4.33 (q, J = 7.1 Hz, 2H), 4.27 (t, J = 6.6 Hz, 2H), 3.88 (s, 6H), 3.65(t, J = 4.6 Hz, 4H), 2.84 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 4.6 Hz, 4H),1.36 (t, J = 7.1 Hz, 3H). 11

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- ethyl-7-(1-(1-(methylsulfonyl)azetidin- 3-yl)-1H-pyrazol-4- yl)-1,6-naphthyridin-2(1H)-one MS m/z (ESI): 578.4, 580.5 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.78 (s, 1H), 8.64 (br s, 1H), 8.18 (s, 1H), 7.66 (s, 1H), 7.39 (s, 1H),6.66 (s, 1H), 5.24- 5.16 (m, 1H), 4.53-4.38 (m, 6H), 3.96 (s, 6H), 3.06(s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 12

1-(5-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7- yl)pyridin-2- yl)cyclobutane-1-carbonitrile MS m/z (ESI): 535.0, 537.1 [M + H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.29 (s, 1H), 8.93 (s, 1H), 8.45 (s, 1H), 7.74 (s, 2H), 7.65(s, 1H), 6.66 (s, 1H), 4.53-4.38 (m, 2H), 3.97 (s, 6H), 2.96 (s, 2H),2.84 (d, J = 11.8 Hz, 2H), 2.53-2.38 (m, 1H), 2.31-2.18 (m, 1H),1.51-1.32 (m, 3H). 13

3-(2-chloro-3,5- dimethoxyphenyl)-1- ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI): 425.4 [M + H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.73(s, 1H), 7.34 (s, 1H), 6.58 (d, J = 2.2 Hz, 1H), 6.53 (s, 1H), 4.44-4.37(m, 2H), 4.01 (s, 3H), 3.91 (s, 3H), 3.82 (s, 3H), 1.44 (t, J = 6.9 Hz,3H). 14

1-ethyl-3-(2-fluoro- 3,5-dimethoxyphenyl)- 7-(1-methyl-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI): 409.2 [M + H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.18 (br s, 1H), 8.04 (s, 1H),7.83 (s, 1H), 7.31 (s, 1H), 6.60 (s, 1H), 6.58 (s, 1H), 4.40 (q, J = 7.1Hz, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 1.43 (t, J = 7.1 Hz,3H). 15

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- methyl-7-(1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 544.2, 546.2 [M + H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.85 (s, 1H),8.52 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.01 (s, 1H),4.30 (t, J = 6.6 Hz, 2H), 3.97 (s, 6H), 3.71 (s, 3H), 3.55 (t, J = 4.6Hz, 4H), 2.78 (t, J = 6.6 Hz, 2H), 2.44 (t, J = 4.6 Hz, 4H). 16

1-(5-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 2-oxo-1-(tetrahydrofuran-3-yl)- 1,2-dihydro-1,6- naphthyridin-7- yl)pyridin-2-yl)cyclobutane-1- carbonitrile ¹H NMR (500 MHz, CDCl3) δ 9.36 (d, J =2.3 Hz, 1H), 8.91 (s, 1H), 8.46 (dd, J = 8.2, 2.3 Hz, 1H), 8.43 (s, 1H),7.69 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 6.66 (s, 1H), 6.45 (dq, J =10.5, 5.5, 4.4 Hz, 1H), 4.58 (t, J = 8.3 Hz, 1H), 4.31 (dd, J = 10.6,3.9 Hz, 1H), 4.10 (t, J = 10.0 Hz, 1H), 3.97 (s, 6H), 3.86 (td, J =10.1, 6.5 Hz, 1H), 2.97 (dt, J = 12.4, 9.1 Hz, 2H), 2.86-2.76 (m, 2H),2.52-2.36 (m, 3H), 2.21 (dtd, J = 11.6, 9.4, 4.7 Hz, 1H) 17

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7- (1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro- 2H-pyran-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 515.4, 517.4 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H),8.56 (br s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 6.66 (s, 1H),4.26- 4.17 (m, 2H), 4.03 (s, 3H), 3.96 (s, 6H), 3.68-3.58 (m, 2H), 2.93(m, 2H), 1.81 (m, 2H), 1.28-1.23 (m, 1H). 18

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7- (1-(2- morpholinoethyl)-1H-pyrazol-4-yl)-1- (tetrahydrofuran-3-yl)- 1,6-naphthyridin- 2(1H)-one MSm/z (ESI): 300.8 [M/2 + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.74 (s, 1H),8.19 (br s, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 6.65 (s, 1H),6.43- 6.34 (m, 1H), 4.63-4.53 (m, 1H), 4.46 (br s, 2H), 4.28 (dd, J =10.4, 4.0 Hz, 1H), 4.07 (t, J = 9.9 Hz, 1H), 3.96 (s, 6H), 3.89-3.82 (m,1H), 3.81 (br s, 4H), 2.96 (br s, 2H), 2.64 (br s, 4H), 2.43 (m, 2H). 19

1-cyclopentyl-3-(2,6- dichloro-3,5- dimethoxyphenyl)-7-(1-methyl-1H-pyrazol- 4-yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI):499.4, 501.4 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (s, 1H), 8.28 (brs, 1H), 8.02 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 6.64 (s, 1H), 5.47-5.37 (m, 1H), 4.01 (s, 3H), 3.95 (s, 6H), 2.38-2.28 (m, 2H), 2.19-2.11(m, 2H), 2.10-2.03 (m, 2H), 1.82-1.75 (m, 2H). 20

1-(5-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 1-methyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7- yl)pyridin-2- yl)cyclobutane-1-carbonitrile MS m/z (ESI): 521.2, 523.2 [M + H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 9.31 (d, J = 2.2 Hz, 1H), 9.00 (s, 1H), 8.57 (d, J = 7.6 Hz,1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 6.67 (s, 1H), 3.97 (s,6H), 3.87 (s, 3H), 3.04-2.93 (m, 2H), 2.86- 2.79 (m, 2H), 2.52-2.42 (m,1H), 2.28- 2.19 (m, 1H). 21

(R)-3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 7-(1-methyl-1H-pyrazol-4-yl)-1- (tetrahydrofuran-3-yl)- 1,6-naphthyridin- 2(1H)-one MSm/z (ESI): 501.4, 503.4 [M + H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (s,1H), 8.38 (s, 1H), 8.10 (d, J = 0.7 Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H),7.01 (s, 1H), 5.94 (p, J = 8.0 Hz, 1H), 4.31 (q, J = 6.9 Hz, 1H),4.08-3.98 (m, 2H), 3.97 (s, 6H), 3.93 (s, 3H), 3.85 (q, J = 7.5 Hz, 1H),2.28 (q, J = 7.8, 7.3 Hz, 2H). 22

(S)-3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 7-(1-methyl-1H-pyrazol-4-yl)-1- (tetrahydrofuran-3-yl)- 1,6-naphthyridin- 2(1H)-one MSm/z (ESI): 501.2, 503.2 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (s,1H), 8.07 (s, 2H), 8.04 (s, 1H), 7.61 (s, 1H), 6.64 (s, 1H), 6.42-6.35(m, 1H), 4.55 (t, J = 8.6 Hz, 1H), 4.28 (dd, J = 10.4, 4.0 Hz, 1H), 4.07(t, J = 9.9 Hz, 1H), 4.00 (s, 3H), 3.96 (s, 6H), 3.86 (q, J = 9.4, 8.9Hz, 1H), 2.47-2.36 (m, 2H). 23

3-(2-chloro-3,5- dimethoxyphenyl)-1- ethyl-7-(1-(2- morpholinoethyl)-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI): 524.2, 526.2[M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 1H), 8.32 (s, 1H), 8.14 (s,1H), 8.12 (s, 1H), HCO₂H), 7.74 (s, 1H), 7.35 (s, 1H), 6.58 (d, J = 2.8Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 4.76 (t, J = 6.1 Hz, 2H), 4.41 (q, J= 7.2 Hz, 2H), 3.94 (t, J = 4.7 Hz, 4H), 3.91 (s, 3H), 3.82 (s, 3H),3.43 (t, J = 6.1 Hz, 2H), 2.92-2.87 (m, 4H), 1.43 (t, J = 7.1 Hz, 3H).24

3-(2-chloro-3,5- dimethoxyphenyl)-7- (1-methyl-1H-pyrazol- 4-yl)-1-(tetrahydrofuran-3-yl)- 1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 467.0,469.0 [M + H]+. ¹H NMR (500 MHz, CDCl₃) δ 8.74 (s, 1H), 8.30 (s, 1H),8.18 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 6.58 (d, J = 2.7 Hz, 1H), 6.50(d, J = 2.5 Hz, 1H), 6.46-6.40 (m, 1H), 4.58 (t, J = 8.3 Hz, 1H), 4.27(dd, J = 10.6, 3.9 Hz, 1H), 4.07 (t, J = 10.0 Hz, 1H), 4.00 (s, 3H),3.92 (s, 3H), 3.88-3.84 (m, 1H), 3.82 (s, 3H), 2.46 (q, J = 10.3, 7.6Hz, 1H), 2.38-2.27 (m, 1H).

Example 25. Preparation of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

3-bromo-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one(50 mg, 0.15 mmol) and2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan(180 mg, 0.60 mmol) were dissolved in a mixed solution of 1,4-dioxane (5mL) and water (1 mL). Thenchloro(2-bicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-diphenyl)[2-(2′-amino-1,1′-diphenyl)]palladium(II)(12 mg, 0.015 mmol) and K₃PO₄ (127 mg, 0.60 mmol) were added. Thereaction solution was stirred at 60° C. for 16 hours. Afterwards, thereaction solution was cooled down to room temperature, added with waterand extracted with ethyl acetate. The organic phase was concentrated andthe residue was separated by column chromatography (ethylacetate/dichloromethane=0˜50%) to obtain3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one(38 mg, yield: 59%). MS m/z (ESI): 427.0 [M+H]+.

¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.04 (d, J=4.5 Hz, 2H), 7.80 (s,1H), 7.31 (s, 1H), 6.71 (t, J=8.0 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.00(s, 3H), 3.91 (s, 6H), 1.43 (t, J=7.1 Hz, 3H).

Examples 26˜41 were Prepared According to the Synthesis Method ofExample 25

Example MS m/z (ESI): [M + H]⁺/ No. Structural Formula Chemical name¹HNMR 26

3-(2,6-difluoro-3,5- dimethoxyphenyl)-1- isopropyl-7-(1-methyl-1H-pyrazol-4- yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 441.4[M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.22 (s, 1H), 8.03 (s,1H), 7.75 (s, 1H), 7.53 (s, 1H), 6.71 (t, J = 8.0 Hz, 1H), 5.34-5.28 (m,1H), 4.01 (s, 3H), 3.91 (s, 6H), 1.72 (t, J = 6.9 Hz, 6H). 27

1- (cyclopropylmethyl)- 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1-methyl-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI):453.3 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.17 (br s, 1H),8.05 (s, 1H), 7.81 (s, 1H), 7.45 (s, 1H), 6.71 (t, J = 8.0 Hz, 1H), 4.29(d, J = 7.0 Hz, 2H), 4.01 (s, 3H), 3.91 (s, 6H), 1.30-1.25 (m, 1H),0.63-0.56 (m, 4H). 28

3-(2,6-difluoro-3,5- dimethoxyphenyl)-7- (1-methyl-1H- pyrazol-4-yl)-1-(tetrahydrofuran-3- yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 469.0[M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.74 (s, 1H), 8.10 (s, 2H), 8.08 (s,1H), 7.76 (s, 1H), 6.72 (t, J = 7.9 Hz, 1H), 6.48- 6.37 (m, 1H), 4.56(t, J = 8.2 Hz, 1H), 4.28 (dd, J = 10.6, 3.9 Hz, 1H), 4.06 (t, J = 10.0Hz, 1H), 4.00 (s, 3H), 3.91 (s, 6H), 3.90-3.80 (m, 1H), 2.50- 2.31 (m,2H). 29

3-(2,6-difluoro-3,5- dimethoxyphenyl)-1- ethyl-7-(1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 526.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.17 (s,1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.32 (s, 1H), 6.71 (t, J = 8.0 Hz, 1H),4.40 (q, J = 7.1, 6.3 Hz, 4H), 3.91 (s, 6H), 3.79-3.72 (m, 4H), 2.98 (s,2H), 2.58 (s, 4H), 1.43 (t, J = 7.1 Hz, 3H). 30

3-(2,6-difluoro-3,5- dimethoxyphenyl)-1- isopropyl-7-(1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 540.5 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 8.15 (s,1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.51 (s, 1H), 6.70 (t, J = 8.0 Hz, 1H),5.31 (s, 1H), 4.37 (t, J = 6.5 Hz, 2H), 3.91 (s, 6H), 3.74 (t, J = 4.6Hz, 4H), 2.95 (t, J = 6.6 Hz, 2H), 2.56 (t, J = 4.6 Hz, 4H), 1.72 (d, J= 6.9 Hz, 6H). 31

1- (cyclopropylmethyl)- 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7- (1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 552.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.23 (s,1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 6.71 (t, J = 7.9 Hz, 1H),4.49 (s, 2H), 4.28 (d, J = 6.9 Hz, 2H), 3.91 (s, 6H), 3.84-3.74 (m, 4H),3.08 (s, 2H), 2.65 (s, 4H), 1.33-1.23 (m, 1H), 0.63-0.55 (m, 4H). 32

1-(5-(3-(2,6-difluoro- 3,5- dimethoxyphenyl)-2- oxo-1-(tetrahydrofuran-3- yl)-1,2-dihydro-1,6- naphthyridin-7- yl)pyridin-2-yl)cyclobutane-1- carbonitrile MS m/z (ESI): 544.8 [M + H]⁺. ¹H NMR (500MHz, CDCl₃) δ 9.40 (s, 1H), 8.96 (s, 1H), 8.49 (s, 2H), 7.88 (s, 1H),7.71 (s, 1H), 6.74 (s, 1H), 6.52 (brs, 1H), 4.59 (t, J = 8.3 Hz, 1H),4.31 (dd, J = 10.6, 3.9 Hz, 1H), 4.10 (t, J = 10.0 Hz, 1H), 3.93 (s,6H), 3.86 (s, 1H), 2.98 (dt, J = 12.4, 9.1 Hz, 2H), 2.86-2.76 (m, 2H),2.52-2.36 (m, 3H), 2.24-2.20 (m, 1H) 33

1-cyclopentyl-3-(2,6- difluoro-3,5- dimethoxyphenyl)-7- (1-methyl-1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z (ESI): 467.2 [M + H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.75 (s, 1H), 8.41 (s, 1H), 8.02 (s, 1H), 7.76(s, 1H), 7.51 (s, 1H), 6.72 (t, J = 8.0 Hz, 1H), 5.53-5.45 (m, 1H), 4.02(s, 3H), 3.91 (s, 6H), 2.35-2.28 (m, 2H), 2.18- 2.07 (m, 2H), 2.12-2.04(m, 2H), 1.86-1.80 (m, 2H). 34

1-cyclopentyl-3-(2,6- difluoro-3,5- dimethoxyphenyl)-7- (1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)- one MS m/z(ESI): 565.8 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.72 (s, 1H), 8.13 (s,1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 6.70 (t, J = 8.0 Hz, 1H),5.57-5.50 (m, 1H), 4.34 (t, J = 6.6 Hz, 2H), 3.91 (s, 6H), 3.72 (t, J =4.6 Hz, 4H), 3.71-3.64 (m, 4H), 2.91 (t, J = 6.5 Hz, 2H), 2.36-2.30 (m,2H), 2.18-2.11 (m, 2H), 2.10-2.03 (m, 2H), 1.84-1.78 (m, 2H). 35

3-(2,6-difluoro-3,5- dimethoxyphenyl)-7- (1-(2- morpholinoethyl)-1H-pyrazol-4-yl)-1- (tetrahydrofuran-3- yl)-1,6-naphthyridin- 2(1H)-one MSm/z (ESI): 567.8 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.74 (s, 1H), 8.17(br s, 1H), 8.10 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 6.72 (t, J = 8.0Hz, 1H), 6.47-6.39 (m, 1H), 4.57 (t, J = 8.8 Hz, 1H), 4.42 (br s, 2H),4.28 (m, 1H), 4.05 (t, J = 10.0 Hz, 1H), 3.92 (s, 6H), 3.87-3.83 (m,1H), 3.85- 3.61 (m, 4H), 2.96 (brs, 2H), 2.53 (br s, 4H), 2.41 (m, 2H).36

3-(2,6-difluoro-3,5- dimethoxyphenyl)-7- (pyridin-3-yl)-1-(tetrahydrofuran-3- yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 466.2[M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.33 (s, 1H), 8.83 (s, 1H),8.67-8.62 (m, 1H), 8.43 (dt, J = 7.9, 1.9 Hz, 1H), 8.38 (s, 1H), 7.78(s, 1H), 7.49-7.44 (m, 1H), 6.66 (t, J = 8.0 Hz, 1H), 6.41 (qd, J = 6.4,3.7 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.23 (dd, J = 10.7, 3.8 Hz, 1H),4.06-3.98 (m, 1H), 3.85 (s, 6H), 3.78 (ddd, J = 11.0, 9.5, 6.5 Hz, 1H),2.42 (dddd, J = 12.4, 10.3, 6.5, 1.9 Hz, 1H), 2.32 (ddt, J = 13.1, 11.1,8.1 Hz, 1H). 37

3-(2,6-difluoro-3,5- dimethoxyphenyl)-7- (4-methylpyridin-3- yl)-1-(tetrahydrofuran-3- yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 480.2[M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.86 (s, 1H), 8.55 (s, 1H), 8.53 (d,J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.46 (d, J = 5.1 Hz, 1H),6.67 (t, J = 8.0 Hz, 1H), 6.40-6.30 (m, 1H), 4.37 (td, J = 8.8, 8.4, 2.0Hz, 1H), 4.16 (dd, J = 10.5, 4.1 Hz, 1H), 3.98 (t, J = 9.9 Hz, 1H), 3.86(s, 6H), 3.72 (ddd, J = 10.9, 9.4, 6.3 Hz, 1H), 2.46 (s, 3H), 2.38(dddd, J = 12.4, 10.0, 6.2, 1.9 Hz, 1H), 2.26 (ddt, J = 12.9, 10.8, 8.0Hz, 1H). 38

7-(6-(2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)pyridin- 3-yl)-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1- (tetrahydrofuran-3-yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 563.2 [M + H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.87 (s, 1H), 8.74 (s, 1H), 8.23 (s, 1H), 8.16 (s,1H), 7.72 (s, 1H), 6.65 (t, J = 8.0 Hz, 1H), 6.47 (s, 1H), 6.37 (dd, J =12.3, 4.6 Hz, 1H), 4.70 (s, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.22 (dd, J =10.5, 4.0 Hz, 1H), 3.99 (t, J = 10.0 Hz, 1H), 3.88 (s, 2H), 3.85 (s,6H), 3.82-3.75 (m, 2H), 3.54 (s, 1H), 3.46-3.41 (m, 1H), 2.39- 2.33 (m,2H), 2.00-1.94 (m, 2H). 39

3-(2,6-difluoro-3,5- dimethoxyphenyl)-7- (pyridin-4-yl)-1-(tetrahydrofuran-3- yl)-1,6-naphthyridin- 2(1H)-one MS m/z (ESI): 466.4[M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.92 (s, 1H), 8.79 (d, J = 5.0 Hz,2H), 8.54 (s, 1H), 8.09 (d, J = 5.5 Hz, 2H), 7.86 (s, 1H), 6.74 (t, J =8.0 Hz, 1H), 6.54- 6.48 (m, 1H), 4.60 (t, J = 8.9 Hz, 1H), 4.33-4.30 (m,1H), 4.10 (t, J = 10.1 Hz, 1H), 3.93 (s, 6H), 3.90-3.83 (m, 1H),2.54-2.28 (m, 1H), 2.41-2.33 (m, 1H). 40

2-(5-(3-(2,6-difluoro- 3,5- dimethoxyphenyl)-2- oxo-1-(tetrahydrofuran-3- yl)-1,2-dihydro-1,6- naphthyridin-7-yl)pyridin-2-yl)-2- methylpropanenitrile MS m/z (ESI): 533.4 [M + H]⁺.¹H NMR (500 MHz, CDCl₃) δ 9.35- 9.31 (m, 1H), 8.92 (s, 1H), 8.51 (dd, J= 8.3, 2.4 Hz, 1H), 8.47 (s, 1H), 7.85 (s, 1H), 7.76 (d, J = 8.2 Hz,1H), 6.74 (t, J = 8.0 Hz, 1H), 6.56-6.45 (m, 1H), 4.60 (t, J = 8.8 Hz,1H), 4.30 (dd, J = 10.7, 3.7 Hz, 1H), 4.08 (t, J = 10.0 Hz, 1H), 3.93(s, 6H), 3.89-3.81 (m, 1H), 2.55-2.45 (m, 1H), 2.42-2.34 (m, 1H), 1.83(s, 6H). 41

2-(4-(3-(2,6-difluoro- 3,5- dimethoxyphenyl)-2- oxo-1-(tetrahydrofuran-3- yl)-1,2-dihydro-1,6- naphthyridin-7-yl)phenyl)acetonitrile MS m/z (ESI): 504.5 [M + H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.92 (s, 1H), 8.41 (s, 1H), 8.17 (d, J = 7.9 Hz, 2H), 7.85 (s,1H), 7.52 (d, J = 7.8 Hz, 2H), 6.73 (t, J = 7.9 Hz, 1H), 6.54- 6.45 (m,1H), 4.57 (t, J = 8.7 Hz, 1H), 4.32 (m, 1H), 4.10 (t, J = 10.0 Hz, 1H),3.93 (s, 6H), 3.89-3.86 (m, 1H), 3.85 (s, 2H), 2.52-2.45 (m, 1H), 2.45-2.35 (m, 1H).

Example 42. Preparation of3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

Step 1: Synthesis of3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

An aqueous solution of [1,1′-bis(biphenylphosphino)ferrocene]palladiumbichloride (80 mg, 0.11 mmol) and Na₂CO₃ (3.0 mL, 6.0 mmol, 2N) wasadded into a solution of 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (450 mg,1.09 mmol) and 3-methylpyrazol-4-borate pinacol ester (340 mg, 1.63mmol) in 1,4-dioxane (15 mL). The reaction solution was stirred at 90°C. for 16 hours. Afterwards, the reaction solution was cooled down toroom temperature, added with water and extracted with ethyl acetate. Theorganic phase was concentrated and the residue was separated by columnchromatography (MeOH/DCM=0˜5%) to obtain3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one(310 mg, yield: 62%). MS m/z (ESI): 459.0, 461.0[M+H]⁺.

Step 2: Synthesis of3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one

Cesium carbonate (355 mg, 1.09 mmol) was added into a solution of3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one(100 mg, 0.218 mmol) and 4-(2-bromoethyl) morpholine bromide (119 mg,0.435 mmol) in DMF (5 mL). The reaction solution was stirred at 90° C.for 2 hours. Then the reaction solution was added with saturated saltsolution, filtered and concentrated. The residue was separated by columnchromatography (MeOH/DCM=0˜8%) to obtain crude product (80 mg). Thecrude product was further separated by SFC to obtain3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one.MS m/z (ESI): 572, 574 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.33(s, 1H), 6.64 (s, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.25 (t, J=6.7 Hz, 2H),3.96 (s, 6H), 3.71 (t, J=4.6 Hz, 4H), 2.87 (t, J=6.8 Hz, 2H), 2.60 (s,3H), 2.52 (t, J=4.7 Hz, 4H), 1.43 (t, J=7.1 Hz, 3H).

Examples 43˜52 were Prepared According to the Synthesis Method ofExample 42

Ex- ample No. Structural Formula Chemical name MS m/z (ESI): [M +H]⁺/¹HNMR 43

2-(4-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-3- methyl-1H-pyrazol-1- yl)acetonitrileMS m/z (ESI): 498.2, 500.2 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s,1H), 8.10 (s, 1H), 7.67 (s, 1H), 7.35 (s, 1H), 6.64 (s, 1H), 5.08 (s,2H), 4.39 (q, J = 7.1 Hz, 2H), 3.95 (s, 6H), 2.61 (s, 3H), 1.43 (t, J =7.1 Hz, 3H). 44

3-(4-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-3- methyl-1H-pyrazol-1-yl)propanenitrile MS m/z (ESI): 512.4, 514.4 [M + H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.81 (s, 1H), 8.34 (s, 1H), 7.67 (s, 1H), 7.37 (s, 1H), 6.65(s, 1H), 4.41 (dt, J = 13.2, 6.8 Hz, 4H), 3.96 (s, 6H), 3.02 (t, J = 6.6Hz, 2H), 2.61 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H). 45

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7-(1- (2- (dimethylamino)ethyl)-3-methyl-1H-pyrazol-4- yl)-1-ethyl-1,6- naphthyridin-2(1H)-one MS m/z(ESI): 530.4, 532.4 [M + H]⁺. ¹HH NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H),8.11 (s, 1H), 7.65 (s, 1H), 7.33 (s, 1H), 6.65 (s, 1H), 4.49 (t, J = 6.5Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.96 (s, 6H), 3.18 (s, 2H), 2.60 (s,3H), 2.51 (s, 6H), 1.43 (t, J = 7.0 Hz, 3H). 46

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- ethyl-7-(3-methyl-1-(1-methylpyrrolidin-3-yl)- 1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)-one MSm/z (ESI): 542.4, 544.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s,1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 6.65 (s, 1H), 5.26-5.17(m, 1H), 4.42-4.29 (m, 2H), 3.96 (s, 6H), 3.62- 3.50 (m, 2H), 3.12-3.09(m, 2H), 2.88- 2.80 (m, 1H), 2.59 (s, 3H), 2.47-2.29 (m, 1H), 2.01 (s,3H), 1.43 (t, J = 6.8 Hz, 3H). 47

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- methyl-7-(3-methyl-1-(2-morpholinoethyl)- 1H-pyrazol-4-yl)-1,6- naphthyridin-2(1H)-one MS m/z(ESI): 558.0, 560.0 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H),8.05 (s, 1H), 7.65 (s, 1H), 7.31 (s, 1H), 6.65 (s, 1H), 4.31 (s, 2H),3.96 (s, 6H), 3.77 (s, 3H), 3.75 (s, 4H), 2.95 (s, 2H), 2.61 (s, 3H),2.58 (s, 4H). 48

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7-(1- (2- (dimethylamino)ethyl)-1H-pyrazol-4-yl)-1- (tetrahydrofuran-3-yl)- 1,6-naphthyridin-2(1H)- oneMS m/z (ESI): 558.2, 560.2 [M + H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (s,1H), 8.23 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 6.65 (s,1H), 6.36 (d, J = 8.9 Hz, 1H), 4.68-4.62 (m, 1H), 4.60-4.54 (m, 1H),4.27 (dd, J = 10.3, 4.2 Hz, 1H), 4.07 (t, J = 9.9 Hz, 1H), 3.96 (s, 6H),3.86 (q, J = 9.2 Hz, 2H), 3.35 (s, 2H), 2.57 (s, 6H), 2.45-2.39 (m, 2H).49

3-(2,6-dichloro-3,5- dimethoxyphenyl)-1- ethyl-7-(5-methyl-1-(2-morpholinoethyl)-1H- pyrazol-4-yl)-1,6- naphthyridin-2(1H)-one MS m/z(ESI): 572.4, 574.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H),7.90 (s, 1H), 7.66 (s, 1H), 7.30 (s, 1H), 6.64 (s, 1H), 4.39 (m, 2H),4.27 (t, J = 7.0 Hz, 2H), 3.95 (s, 6H), 3.71 (t, J = 4.6 Hz, 4H), 2.84(t, J = 6.9 Hz, 2H), 2.70 (s, 3H), 2.53 (t, J = 4.5 Hz, 4H), 1.42 (t, J= 7.0 Hz, 3H). 50

2-(4-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-5- methyl-1H-pyrazol-1- yl)acetonitrileMS m/z (ESI): 498.2, 500.3 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s,1H), 7.95 (s, 1H), 7.67 (s, 1H), 7.31 (s, 1H), 6.64 (s, 1H), 5.11 (s,2H), 4.39 (m, 2H), 3.95 (s, 6H), 2.78 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).51

3-(4-(3-(2,6-dichloro- 3,5-dimethoxyphenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-5- methyl-1H-pyrazol-1-yl)propanenitrile MS m/z (ESI): 512.4, 514.4 [M + H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.84 (s, 1H), 7.99 (s, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 6.65(s, 1H), 4.48-4.37 (m, 4H), 3.96 (s, 6H), 3.02 (t, J = 6.6 Hz, 2H), 2.75(s, 3H), 1.42 (d, J = 7.0 Hz, 3H). 52

3-(2,6-dichloro-3,5- dimethoxyphenyl)-7-(1- (2- (dimethylamino)ethyl)-5-methyl-1H-pyrazol-4- yl)-1-ethyl)-1,6- naphthyridin-2(1H)-one MS m/z(ESI): 530.4, 532.4 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H),7.92 (s, 1H), 7.66 (s, 1H), 7.29 (s, 1H), 6.65 (s, 1H), 4.50 (t, J = 6.8Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.96 (s, 6H), 3.19 (t, J = 6.5 Hz,2H), 2.75 (s, 3H), 2.54 (s, 6H), 1.42 (t, J = 7.1 Hz, 3H).

Biological Test Evaluation I. In Vitro Biochemical Kinase Assay of FGFR1˜3

Caliper Assay was used in the present invention to determine theinhibitory activities of the compounds against FGFR1, FGFR2, and FGFR3.The specific experimental procedure was as follows:

1. The kinase reaction in the present invention was carried out in384-well plates, the kinase (Carna) at a certain concentration and ATPat a certain concentration and 1 μM of peptide FAM-P22 (GL Biochem, Cat.No. 112393)) was incubated to react for a certain time at 28° C. in areaction system consisting of 50 mM HEPES, pH7.5, 0.0015% Brij-35 andbasic kinase buffer; for FGFR1, the enzyme concentration was 0.25 nM andATP concentration was 382 μM and the reaction time was 20 minutes; forFGFR2, the enzyme concentration was 2.5 nM, ATP concentration was 1 μM,and the reaction time was 40 minutes; for FGFR3, the enzymeconcentration was 8 nM, ATP concentration was 4.704, and the reactiontime was 30 minutes;

2. The reaction was terminated with a stop solution (100 mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50 mM EDTA and 0.0015% Brij35);

3. The plate with the terminated kinase reaction was transferred to theCaliper workstation to read the data;

4. the phosphorylated and unphosphorylated peptides were separated bythe Caliper microfluid migration shift technique, and the analyte wastransferred by a constant buffer flow through the chip, the migration ofthe substrate peptide was monitored by the labeled fluorescent signal,and the kinase activity was calculated by the amount of thephosphate-based peptide formed.

5. IC₅₀ was determined by non-linear regression analysis of percentinhibition at different concentration level of the compound. Theenzymatic activities of the compound in the specific examples were shownin Table 1.

TABLE 1 Enzymatic activity test results Example Enzymatic activityIC₅₀(nM) No. FGFR1 FGFR2 FGFR3 1 +++ +++++ NT 2 +++ ++++ ++ 3 ++++ +++++NT 4 +++ +++++ NT 5 ++ +++ NT 6 NT NT NT 7 +++++ +++++ NT 8 NT NT NT 9+++ +++++ NT 10 +++ +++++ +++++ 11 +++ +++++ NT 12 NT NT NT 13 ++ ++++NT 14 NT NT NT 15 ++ ++++ ++ 16 ++ +++ NT 17 NT NT NT 18 NT NT NT 19 NTNT NT 20 NT NT NT 21 ++++ +++++ +++++ 22 +++++ +++++ NT 23 NT NT NT 24NT NT NT 25 +++++ +++++ NT 26 NT NT NT 27 NT NT NT 28 +++++ +++++ NT 29++++ +++++ NT 30 +++++ +++++ NT 31 NT NT NT 32 ++++ +++++ NT 33 ++++++++++ NT 34 NT NT NT 35 NT NT NT 36 NT NT NT 37 NT NT NT 38 NT NT NT 39NT NT NT 40 ++++ +++++ NT 41 NT NT NT 42 NT NT NT 43 NT NT NT 44 NT NTNT 45 NT NT NT 46 +++ +++++ NT 47 NT NT NT 48 +++ +++++ NT 49 NT NT NT50 NT NT NT 51 NT NT NT 52 NT NT NT Note 1. “NT”, i.e., “Not Tested”,means that the compound was not tested. 2. “+++++” means biologicalactivity IC₅₀ ≤ 5.0 nM; “++++” means 5.0 nM < biological activity IC₅₀ ≤10.0 nM; “+++” means 10.0 nM < biological activity IC₅₀ ≤ 50.0 nM; “++”means 50.0 nM < biological activity IC₅₀ ≤ 500.0 nM; “+” means 500.0 nM< biological activity IC₅₀.

II. Cell Proliferation Assay (Cell Titer Glo (CTG) Assay

The FGFR signal pathway dependent inhibitory effect of the compound inthe present invention on cell proliferation was assessed by survivaltest using CTG reagent (Promega, #G7573). Cell lines representative of avariety of tumor types, including H1581 lung cancer cells (FGFR1 geneamplification), Snu-16 gastric cancer cells (FGFR2 gene amplification),and RT112 bladder carcinoma cells (FGFR3-TACC3 fusion) from NanjingCobioer Biosciences, were selected for the assay. The specificexperimental procedure was as follows:

1. 90 μL of cells were seeded into a 96-well plate processed with TCM(Costar 43904), and incubated overnight at 37° C. in a 5% CO₂ incubator;afterwards, 10 μL of the culture medium containing the compound at 10fold of its final concentration was added;

2. The dose-dependent effect was evaluated by a serial dilution of thetest compound, starting from 10 μM or a lower concentration.

3. The cells were incubated at 37° C. under 5% CO₂ for 3 days, thenadded 50 μL, CTG, and read the data with Envision (Pelkin Elmer) toquantify the ATP level in the cells. The ATP levels in cells withtreatment of inhibitor at a variety of concentrations were compared withthose in cells of the control group (in which DMSO was added into themedium) to evaluate the compound percent inhibition of cellproliferation/survival.

4. The compound half growth inhibitory concentration (IC₅₀) wasdetermined in Graphpad Prism by 4-parameter curve fitting. The cellularactivities of the compound in specific examples were shown in Table 2.

TABLE 2 Cellular Activity test results Example Cellular IC₅₀ (nM) No.Sun16 H1581 RT112 1 NT NT NT 2 +++ ++ ++ 3 NT NT NT 4 ++ ++ NT 5 +++ ++NT 6 NT NT NT 7 ++++ +++ NT 8 NT NT NT 9 NT NT NT 10 +++ ++ +++ 11 +++++ NT 12 ++ + NT 13 NT NT NT 14 NT NT NT 15 +++ ++ ++ 16 +++ ++ ++ 17++++ ++ NT 18 6.0 ++ 4.1 19 NT NT NT 20 ++ + NT 21 ++++ ++ NT 22 ++++++++ NT 23 NT NT NT 24 +++ ++ NT 25 ++ ++ NT 26 +++ +++ NT 27 NT NT NT 28+++++ +++ +++++ 29 +++ ++ NT 30 +++++ +++ NT 31 +++ ++ NT 32 10.7  ++2.5 33 +++++ +++ NT 34 +++++ +++ +++++ 35 ++++ ++ +++++ 36 +++ ++ NT 37++ + NT 38 +++++ +++ NT 39 ++ ++ NT 40 ++++ ++ NT 41 ++ ++ NT 42 +++ ++NT 43 NT NT NT 44 ++ ++ NT 45 +++ ++ NT 46 +++ ++ NT 47 ++ ++ NT 48 ++++++ NT 49 ++ ++ NT 50 + + NT 51 ++ + NT 52 ++ + NT Note 1. “NT”, i.e.,“Not Tested”, means that the compound was not tested. 2. “+++++” meansbiological activity IC₅₀ ≤ 5.0 nM; “++++” means 5.0 nM < biologicalactivity IC₅₀ ≤ 10.0 nM; “+++” means 10.0 nM < biological activity IC₅₀≤ 50.0 nM; “++” means 50.0 nM < biological activity IC₅₀ ≤ 500.0 nM; “+”means 500.0 nM < biological activity IC₅₀.

It can be seen from the enzymatic activity data or cellular activitydata of the compounds of the specific examples that the compounds of thepresent invention had a strong inhibitory effect on the enzymaticactivity FGFR kinases, especially on the enzymatic activity of FGFR2and/or FGFR3 kinases. The compounds are expected to be developed into anew generation of FGFR inhibitors to meet clinical needs.

All documents mentioned in the present invention are hereby incorporatedby reference in their entirety, just as each document is citedseparately as a reference. In addition, it should be understood thatvarious modifications and changes may be made by those skilled in theart after reading the above teachings of the present invention and theseequivalent forms also fall within the scope defined by the claimsappended hereto.

1. A compound of formula (I), a stereoisomer, prodrug orpharmaceutically acceptable salt thereof:

wherein, X is CH or N; R₁ is selected from the group consisting of H,deuterium, hydroxy, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, —S(O)R₅, —S(O)₂R₆ and —C(O)R₇, above groups are optionallyfurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂; R₂is selected from the group consisting of C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl and —NR₈R₉, abovegroups are optionally further substituted by one or more substituentsselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;each R₃ is independently selected from the group consisting of H,deuterium, halogen, cyano, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,above groups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;each R₄ is independently selected from the group consisting of H,deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(═NR₁₃)R₁₂, —C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and—C₀₋₈—N(R₁₃)—C(O)R₁₂, above groups are optionally further substituted byone or more substituents selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl,3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂; R₅and R₆ are each independently selected from the group consisting of H,deuterium, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl, 3-10 memberedheterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10membered heteroaryloxy and —NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, oxo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄; R₇ is selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 memberedheterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy,5-10 heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄, above groupsare optionally further substituted by one or more substituents selectedfrom the group consisting of deuterium, halogen, hydroxy, cyano, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 memberedheterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy,5-10 heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄; R₈ and R₉ areeach independently selected from the group consisting of deuterium,hydroxy, C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —S(O)_(r)R₁₀, —C(O)R₁₂ and—C(O)NR₁₃R₁₄, above groups are optionally further substituted by one ormore substituents selected from the group consisting of deuterium,halogen, cyano, nitro, azido, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl, C₃₋₁₀ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, ═O,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂,or, R₈ and R₉, together with the nitrogen atom directly attachedthereto, form a 4-10 membered heterocyclyl, above groups are optionallyfurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, ═O, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(═NR₁₃)R₁₂,—C₀₋₈—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₈—C(O)NR₁₃R₁₄ and —C₀₋₈—N(R₁₃)—C(O)R₁₂;each R₁₀ is selected from the group consisting of H, deuterium, hydroxy,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy,C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 membered heteroaryl, 5-10 memberedheteroaryloxy and —NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, oxo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄; each R₁₁ isselected from the group consisting of H, deuterium, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl and5-10 membered heteroaryl, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, oxo, cyano, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 memberedheterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy,5-10 heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄; each R₁₂ isselected from the group consisting of H, deuterium, hydroxy, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl,C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl, 3-10 memberedheterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10membered heteroaryloxy and —NR₁₃R₁₄, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, cyano, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy and —NR₁₃R₁₄; R₁₃ and R₁₄ areeach independently selected from the group consisting of H, deuterium,hydroxy, C₁₋₁₀ alkoxy, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl,cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl,dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino and C₁₋₁₀alkanoyl, above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,hydroxy, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl,C₁₋₁₀ deuterioalkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy,3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C₅₋₁₀ aryl,C₅₋₁₀ aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxy, amino,monoalkylamino, dialkylamino and C₁₋₁₀ alkanoyl, or, R₁₃ and R₁₄,together with the nitrogen atom directly attached thereto, form a 4-10membered heterocyclyl or 4-10 membered heteroaryl, above groups areoptionally further substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, hydroxy, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ deuterioalkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkoxy, 3-10 membered heterocyclyl,3-10 membered heterocyclyloxy, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, 5-10heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino,dialkylamino and C₁₋₁₀ alkanoyl; each r is independently 0, 1 or
 2. 2.The compound of formula (I), the stereoisomer, prodrug orpharmaceutically acceptable salt thereof of claim 1, wherein, R₁ isselected from the group consisting of H, deuterium, hydroxy, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,C₅₋₈ aryl, 5-8 membered heteroaryl, —S(O)R₅, —S(O)₂R₆ and —C(O)R₇, abovegroups are optionally further substituted by one or more substituentsselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, ═O,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂;R₅, R₆, R₇, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r are defined as in claim
 1. 3.The compound of formula (I), the stereoisomer, prodrug orpharmaceutically acceptable salt thereof of claim 1, wherein, each R₄ isindependently selected from the group consisting of H, deuterium,halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀,—C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂,—C₀₋₄—NR₁₃R₁₁, —C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂,—C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ andr are defined as in claim
 1. 4. The compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof ofclaim 1, wherein, each R₃ is independently selected from the groupconsisting of H, deuterium, halogen, cyano, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8membered heteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂,above groups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CM deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,C₅₋₈ aryl, 5-8 membered heteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁,—C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄,—C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and—C₀₋₄—N(R₁₃)—C(O)R₁₂; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r are defined as inclaim
 1. 5. The compound of formula (I), the stereoisomer, prodrug orpharmaceutically acceptable salt thereof of claim 1, wherein, R₂ is C₅₋₈aryl or 5-8 membered heteroaryl, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈aryl, 5-8 membered heteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁,—C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄,—C₀₋₄—C(═NR₁₃)R₁₂, —C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and—C₀₋₄—N(R₁₃)—C(O)R₁₂, above groups are optionally more furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, ═O, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(═NR₁₃)R₁₂,—C₀₋₄—N(R₁₃)—C(═NR₁₄)R₁₂, —C₀₋₄—C(O)NR₁₃R₁₄ and —C₀₋₄—N(R₁₃)—C(O)R₁₂;R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r are defined as in claim
 1. 6. The compoundof formula (I), the stereoisomer, prodrug or pharmaceutically acceptablesalt thereof of claim 5, wherein, R₂ is phenyl or 5-6 memberedheteroaryl, the 5-6 membered heteroaryl is selected from pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, pyrrolyl,pyrazolyl, imidazolyl, triazol and thiazolyl, above groups areoptionally further substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, C₁₋₄ alkyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, —S(O)_(r)R₁₀, —O—R₁₁, —C(O)OR₁₁,—NR₁₃R₁₄, —C(O)NR₁₃R₁₄ and —N(R₁₃)—C(O)R₁₂, above groups are optionallymore further substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, ═O, —S(O)_(r)R₁₀, —O—R₁₁ and —NR₁₃R₁₄; R₁₀, R₁₁, R₁₂, R₁₃,R₁₄ and r are defined as in claim
 5. 7. The compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof ofclaim 1, the compound of formula (I) is a compound having formula (II):

wherein, X is CH or N; R₁ is selected from the group consisting of H,deuterium, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl,methylsulfonyl and aminosulfonyl, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, F, Cl, cyano, methyl, ethyl, C₃₋₆ cycloalkyl,3-6 membered heterocyclyl, phenyl, methoxy, ethoxy, hydroxy, amino,isopropylamino, dimethylamino and diethyl amino; R₂ is phenyl or 5-6membered heteroaryl, the 5-6 membered heteroaryl is selected from thegroup consisting of pyridyl, pyrazolyl, imidazolyl and thiazolyl, abovegroups are optionally further substituted by one or more substituentsselected from the group consisting of deuterium, halogen, cyano,hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, 3-8 memberedheterocyclyl, —NR₁₃R₁₄ and —C(O)NR₁₃R₁₄, above groups are optionallymore further substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, hydroxy, C₁₋₄ alkoxy,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl, 3-8membered heterocyclyl, —S(O)_(r)R₁₀ and —NR₁₃R₁₄; each R₃ isindependently selected from the group consisting of H, deuterium,halogen, cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, oxacyclobutyl,azacyclopentyl, azacyclohexyl, hydroxy, methoxy, ethoxy and isopropoxy,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, C₁₋₄ alkyl, trifluoromethyl, difluoromethyl, trideuteriomethyl,dideuteriomethyl, cyclopropyl, oxacyclobutyl, methoxy, ethoxy, hydroxyand carboxy; each R₄ is independently selected from the group consistingof H, deuterium, F, Cl, cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,oxacyclobutyl, azacyclopentyl, azacyclohexyl, hydroxy, methoxy, ethoxyand isopropoxy, above groups are optionally further substituted by oneor more substituents selected from the group consisting of deuterium, F,Cl, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy and hydroxy; R₁₀,R₁₃, R₁₄ and r are defined as in claim
 1. 8. The compound of formula(I), the stereoisomer, prodrug or pharmaceutically acceptable saltthereof of claim 7, wherein, each R₁₀ is selected from the groupconsisting of H, deuterium, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₂₋₄alkenyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, 3-8 membered heterocyclyl,3-8 membered heterocyclyloxy, C₅₋₈ aryl, C₅₋₈ aryloxy, 5-8 memberedheteroaryl, 5-8 membered heteroaryloxy and —NR₁₃R₁₄, above groups areoptionally further substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, hydroxy, oxo, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, 3-8 memberedheterocyclyl, 3-8 membered heterocyclyloxy, C₅₋₈ aryl, C₅₋₈ aryloxy, 5-8membered heteroaryl, 5-8 membered heteroaryloxy and —NR₁₃R₁₄; R₁₃ andR₁₄ are each independently selected from H, deuterium, hydroxy, C₁₋₄alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, sulfinyl,sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl,p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino,monoalkylamino, dialkylamino and C₁₋₄ alkanoyl, above groups areoptionally further substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, hydroxy, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₁₋₄ alkoxy,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, 3-8 membered heterocyclyl, 3-8membered heterocyclyloxy, C₅₋₈ aryl, C₅₋₈ aryloxy, 5-8 memberedheteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino,dialkylamino and C₁₋₄ alkanoyl, or, R₁₃ and R₁₄, together with thenitrogen atom directly attached thereto, form a 4-8 memberedheterocyclyl or 4-8 membered heteroaryl, above groups are optionallyfurther substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, hydroxy, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₁₋₄ alkoxy, C₃₋₈cycloalkyl, C₃₋₈ cycloalkoxy, 3-8 membered heterocyclyl, 3-8 memberedheterocyclyloxy, C₅₋₈ aryl, C₅₋₈ aryloxy, 5-8 membered heteroaryl, 5-8membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C₁₋₄alkanoyl; each r is independently 0, 1 or
 2. 9. The compound of formula(I), the stereoisomer, prodrug or pharmaceutically acceptable saltthereof of claim 1, wherein the compound is selected from the followingcompounds:


10. A process for preparing the compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof ofclaim 1, comprising the following steps:

wherein, X₁ and X₂ are each independently Cl or Br; X, R₁, R₂, R₃ and R₄are defined as in claim
 1. 11. A pharmaceutical composition, comprisingthe compound of formula (I), the stereoisomer, prodrug orpharmaceutically acceptable salt thereof of claim 1, andpharmaceutically acceptable carrier.
 12. A method of treating a tumor orcancer in a subject the method comprising administering to the subjectin need thereof a therapeutically effective amount of the compound offormula (I), the stereoisomer, prodrug or pharmaceutically acceptablesalt thereof of claim
 1. 13. A method of treating myeloproliferativedisease, skeleton or cartilage cell disorder, and hypophosphatemia in asubject the method comprising administering to the subject in needthereof a therapeutically effective amount of the compound of formula(I), the stereoisomer, prodrug or pharmaceutically acceptable saltthereof of claim
 1. 14. The method of claim 13, wherein, themyeloproliferative disease is selected from polycythemia, primarythrombocytosis or primary myelofibrosis; the skeleton or cartilage celldisorder is selected from dysplasia, dyschondroplasia, dwarfism,thanatophoric dysplasia (TD), Apert's syndrome, Crouzon syndrome,Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Pfeiffersyndrome or cranial muscular atrophy syndrome; the hypophosphatemia isselected from X-linked hypophosphatemic rickets, autosomal recessivehypophosphatemic rickets, autosomal dominant hypophosphatemic ricketsand tumor induced oothecomalacia.
 15. The compound of formula (I), thestereoisomer, prodrug or pharmaceutically acceptable salt thereof ofclaim 1 for use as an FGFR inhibitor for the treatment of diseasesrelated to the aberrant expression/mutation of FGFR or the aberrantexpression/activity of corresponding ligand(s).
 16. The compound offormula (I), the stereoisomer, prodrug or pharmaceutically acceptablesalt thereof of claim 2, wherein R₁ is selected from the groupconsisting of H, deuterium, C₁₋₄ alkyl, allyl, C₃₋₆ cycloalkyl, 3-6membered heterocyclyl, phenyl, diazole, triazol, methylsulfonyl,isopropylsulfonyl, aminosulfonyl, methoxycarbonyl, ethoxycarbonyl,acetyl, aminocarbonyl and dimethylaminocarbonyl, above groups areoptionally further substituted by one or more substituents selected fromthe group consisting of deuterium, F, Cl, cyano, methyl, ethyl, C₃₋₆cycloalkyl, 3-6 membered heterocyclyl, phenyl, methoxy, ethoxy, hydroxy,amino, isopropylamino, dimethylamino and diethyl amino.
 17. The compoundof formula (I), the stereoisomer, prodrug or pharmaceutically acceptablesalt thereof of claim 3, wherein each R₄ is independently selected fromthe group consisting of H, deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, allyl, acetenyl, C₃₋₆ cycloalkyl, oxacyclobutyl, azacyclopentyl,azacyclohexyl, phenyl, diazole, triazol, methylsulfonyl,isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy,methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino,dimethylamino and acetylamino, above groups are optionally furthersubstituted by one or more substituents selected from the groupconsisting of deuterium, F, Cl, cyano, methyl, ethyl, cyclopropyl,phenyl, methoxy, ethoxy, hydroxy and amino.
 18. The compound of formula(I), the stereoisomer, prodrug or pharmaceutically acceptable saltthereof of claim 5, wherein R₂ is phenyl or 5-6 membered heteroaryl,above groups are optionally further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl, C₅₋₆aryl, 5-6 membered heteroaryl, ═O, —S(O)_(r)R₁₀, —O—R₁₁, —C(O)OR₁₁,—C(O)R₁₂, —O—C(O)R₁₂, —NR₁₃R₁₄, —C(O)NR₁₃R₁₄ and —N(R₁₃)—C(O)R₁₂, abovegroups are optionally more further substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ deuterioalkyl, C₃₋₈ cycloalkyl,3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, ═O,—S(O)_(r)R₁₀, —O—R₁₁, —C(O)OR₁₁, —C(O)R₁₂, —O—C(O)R₁₂, —NR₁₃R₁₄,—C(O)NR₁₃R₁₄ and —N(R₁₃)—C(O)R₁₂; R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and r aredefined as in claim
 5. 19. The method according to claim 12, wherein thetumor or cancer is selected from the group consisting of bladder cancer,breast cancer, cervical cancer, colorectal cancer, endometrial cancer,gastric cancer, head and neck cancer, renal carcinoma, hepaticcarcinoma, lung cancer, ovarian cancer, prostate cancer, esophagealcancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skincancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adultT cell leukemia, B cell lymphoma, acute myelocytic leukemia, Hodgkinlymphoma or non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, hairycell lymphoma, cell lymphoma, Bunkitt's lymphoma, glioblastoma, melanomaand rhabdomyosarcoma.